Alternative pre-mRNA splicing is a critical step in gene expression and regulation. Accumulating evidence indicates that pre-mRNA splicing defects and aberrant splicing are associated with a number of neurodegenerative disorders. For example, aberrant alternative splicing of tau gene due to intronic mutations has been found in certain inherited forms of dementia. This proposal aims to investigate the role of alternative splicing in neurodegeneration by using a tau minigene model system that we have established. We plan to use molecular and biochemical approaches to study the regulatory mechanism underlying tau alternative splicing. We have established both in vitro biochemical assays and cell culture system to examine the effect of newly identified and known splicing regulators on tau alternative splicing. Our preliminary studies have revealed that certain alternative splicing factors may play a role in regulating tau alternative splicing. A primary neuronal culture system has also been set up to investigate the role of identified factors in neuronal cell death. Molecular dissection of cis- and trans-acting elements important for tau alternative splicing will not only help in understanding the basic mechanism controlling tau alternative splicing but also reveal new players in the pathogenesis of neurodegeneration.